Pyrithione (also known as 2-mercaptopyridine-1-oxide, 2-pyridinethiol-1-oxide, and 2-pyridinethione) and monovalent metal salts (Li, Na and K) and polyvalent metal salts (Mg, Ca, Zn and Cu) of pyrithione are well known antimicrobial agents, and widely used as fungicides, bactericides and preservatives/mildewicide in antidandruff shampoo, antifouling paint, metal working fluid, fish-farming net, architecture paints and other industrial, household and building products.
Sodium pyrithione is an important intermediate for producing polyvalent salts of pyrithione, in particular, zinc pyrithione and copper pyrithione, which are widely used as biocides. It has been a challenging task to produce sodium pyrithione more efficiently and economically to meet the increasing market demand.
Scheme 1 shows a conventional method for preparing sodium pyrithione, which includes the steps of: 1) chlorination of pyridine 1 to 2-chloropyridine 2; 2) oxidation of 2 to 2-chloropyridine N-oxide 3; 3) mercaptization of 3 with sodium hydrosulfide or sodium sulfide to sodium pyrithione 4; and 4) complexation of 4 with a divalent metal salt (ML2 where L2=Cl2, SO4; M=Mg, Ca, Sr, Ba, Zn and Cu) to produce metal salts of pyrithione 5.

In scheme 1, mercaptization of 2-chloropyridine N-oxide 3 can be achieved with either sodium sulfide, or sodium hydrosulfide/sodium hydroxide (DE2717325, U.S. Pat. No. 4,080,329). Mercaptization of 3 using sodium sulfide or sodium hydroxide is a clean reaction and generates a nearly quantitative yield of sodium salt of pyrithione 4. Further, metal complexation of resulting 4 with polyvalent metal salt of chloride and sulfate produces the corresponding metal pyrithione 5 having high purity and in high yield (U.S. Pat. Nos. 4,396,766 and 3,159,640).
However, the process shown in scheme 1 includes complex chlorination of pyridine 1 and incomplete oxidation of 2-chloropyridine 2 to produce relative low yield of products. Although unreacted 2-chloropyridine 2 can be recovered, the recovery process requires a costly separation of 2-chloropyridine from reaction mixtures containing either unreacted pyridine and other chlorinated pyridines, or 2-chloropyridine N-oxide and catalyst. Therefore, many efforts have been focused on improving the chlorination and oxidation steps of scheme 1.
2-chloropyridine 2 have been prepared by thermal and photochemical chlorination of 1 (DE2208007; U.S. Pat. No. 3,297,556; U.S. Pat. No. 5,536,376; Jpn Kokai Tokkyo Koho, JP 01 308,255, 1989; J. Chinese medicine industry, 21(7), 317, 1990; and Guangzhou Huaxue (2003), 28(1), 23-25, 58). Both thermal and photochemical chlorination processes are complex, and generally result in a product mixture containing the unreacted pyridine 1, the desired 2-chloropyridine 2, and a mixture of 2,6-dichloropyridine, 3-, 4-, 5-chloropyridine and tar. Sequential purification of 2-chloropyridine from the reaction mixtures is an expensive and lengthy process. Oxidation of 2-chloropyridine 2 to 2-chloropyridine N-oxides 3 is more difficult than chlorination of pyridine 1 to 2 because of electron-withdrawing properties of the chlorine. Early attempts that involved the oxidation of 2 with peroxy acids gave a moderate yield of the product, but multiple recycling of the unreacted starting materials was necessary (U.S. Pat. No. 2,951,844). This oxidation was later improved using peracetic acid, which was generated in situ from hydrogen peroxide and acetic acid, in the presence of a catalyst to give 2-chloropyridine N-oxide 3 in a yield ranging from 40-68%. Catalysts used for this purpose included maleic acid, maleic acid anhydride or phthalic acid anhydride (U.S. Pat. No. 4,504,667), sulfuric acid and sodium hydrosulfate (U.S. Pat. No. 4,585,871), tungstic acid (U.S. Pat. No. 3,047,579), or heterogeneous polymer with sulfonic acid and carboxylic acid moieties (U.S. Pat. No. 5,869,678). U.S. Pat. No. 3,203,957 discloses a process to improve the oxidation of 2, by using 70% hydrogen peroxide, one equivalent of maleic acid anhydride as catalyst, and methylene chloride as a solvent. However, this process does not improve the yield of 3.
The above prior art oxidation methods require complex and costly separation processes, including recovery of large amount of unreacted starting material 2, and disposal or recovery of substantial amount of acetic acid and catalyst. Further, large amount of salts of the acids remaining in the aqueous phase with the 2-chloropyridine N-oxide 3 product causes problems for subsequent reaction steps of Scheme 1.
Another approach for preparing polyvalent metal pyrithione is shown in Scheme 2, which involves three steps starting from pyridine and does not include a chlorination step. Scheme 2 comprises the steps of oxidation of pyridine 1 to pyridine N-oxide 6, sulfurination of 6 with a sulfurinating agent in the presence of a base agent followed by metal complexation of sodium pyrithione 4 with a corresponding polyvalent metal salt to form the corresponding metal pyrithione 5.

Scheme 2 does not involve complex chlorination steps, and it involves a more facile oxidation of pyridine rather than the oxidation of 2-chloropyridine shown in scheme 1. The oxidation of pyridine, as shown in Scheme 2, under similar conditions used for the oxidation of 2-chloropyridine in Scheme 1, results in nearly quantitative yield of pyridine N-oxide 6. Thus, no recovery of pyridine is needed.
One aspect in which the prior art processes differ as to one another is the type of bases used for generating the active carbon anion of pyridine N-oxide 6, which then reacts with a sulfurinating agent to form sodium pyrithione 4. U.S. Pat. Nos. 3,590,035 and 3,700,676 disclose the use of sodium hydride, butyllithium and potassium tert-butoxide for generating the carbon anion of pyridine N-oxide. The resulting carbon anion was treated with elemental sulfur or sulfur chloride to produce sodium or lithium pyrithione, respectively. The bases used in these methods are not cost effective, and the product yield is about 40%. JP 58088362, 59112968 and 58152867 disclose using a weaker base, sodium hydroxide, for generating the carbon anion. According the methods disclosed in JP 58088362, 59112968 and 58152867 pyridine N-oxide 6 was first treated with NaOH to generate the carbon anion of 6 and then reacted with elemental S or SCl in the presence of an organic solvent such as DMF and toluene to form sodium pyrithione having a yield of about 10%, based on the pyridine N-oxide.
Until Zheng et. al. (Huaxue Shijie, 34(9), 437-40, 1993), data on the quality of polyvalent salts of pyrithione made from the direct sulfurination of pyridine N-oxide was unavailable. Zheng et. al. modified scheme 2 and generated sodium pyrithione from reaction of 6 with elemental sulfur and sodium hydroxide in DMSO/toluene. The resulting sodium pyrithione was then converted to zinc pyrithione having brown color and with a yield of about 20% yield. The low yield and the brown color of zinc pyrithione are not acceptable for commercialization applications.
More recently, potassium tert-butoxide was used to generate the carbon anion of pyridine N-oxide 6 in an organic solvent (KR Application No. 10-2000-0062795) and the resulting carbon anion was treated with 30 times of elemental sulfur to produce potassium pyrithione in 65-73% yield. However, potassium pyrithione was not isolated and its quality was not reported. Excess sulfur used in the process is not only expensive, but makes separation of product difficult. More importantly, there is no data of polyvalent metal pyrithione made from this process, and thus the quality, color and purity, of polyvalent metal pyrithiones is unknown.
U.S. Pat. No. 3,773,770 discloses a method for producing sodium pyrithione comprising decarboxylation of 2-picolinic acid N-oxide or its salt to the carbon anion of 6 followed by treatment of 6 with elemental sulfur. Sodium pyrithione generated from this process is converted to polyvalent metal pyrithiones having a low yield of about 40% with unacceptable quality.
Sodium pyrithione and polyvalent pyrithione generated using prior art methods are not cost effective, and do not meet color and purity specifications set for commercial application. For example, zinc pyrithione often requires at least 98% purity with white or off-white color to meet specifications for antidandruff shampoo formulation, and copper pyrithione requires a purity that will not cause gelation of antifouling paint.
Thus, there is a need to overcome the above-stated product quality problems and high cost associated with the processes. In particular, there is a need to provide a better method for producing high yield of sodium pyrithione from pyridine N-oxide that gives high quality of polyvalent metal pyrithione, particularly, zinc pyrithione with white or off white color.